This application is a National Stage application under 35 U.S.C. 371 of PCT/EP98/04194 filed Jul. 7, 1998, which claims priority from EP 97.202.181.0, filed Jul. 11, 1997.
The present invention is concerned with novel 2,4,4-trisubstituted-1,3-dioxolane antifungals and their preparation; it further relates to compositions comprising them, as well as their use as a medicine.
EP-A-0,118,138 discloses 2,2,4-trisubstituted-1,3-dioxolanes having antimicrobial properties and effective in inhibiting the growth of Candida albicans. The compounds of the present invention differ therefrom structurally by the substitution pattern on the 1,3-dioxolane ring.
WO 88/05048 discloses 2,4,4-trisubstituted-1,3-dioxolane derivatives which are taught to have antifungal activity. The present compounds differ therefrom structurally by the nature of the substituent on the 4-(4-phenylpiperazinyl)phenoxymethyl moiety in the 2 position of the 1,3-dioxolane ring.
The present compounds are found to be active against a wide variety of fungi, in particular against dermatophytes.
The present invention concerns novel compounds of formula 
the N-oxide forms, the pharmaceutically acceptable acid addition salts and stereochemically isomeric forms thereof, wherein
n is zero, 1, 2 or 3;
X is N or CH;
each R1 independently is halo, nitro, cyano, amino, hydroxy, C1-4alkyl, C1-4alkyloxy or trifluoromethyl;
R2 is hydrogen; C3-7alkenyl; C3-7alkynyl, aryl; C3-7cycloalkyl; C1-6alkyl or C1-6alkyl substituted with hydroxy, C1-4alkyloxy, C3-7cycloalkyl or aryl;
R3 and R4 each independently are hydrogen, C1-6alkyl, C3-7cycloalkyl or aryl; or
R3 and R4 taken together form a bivalent radical xe2x80x94R3xe2x80x94R4xe2x80x94 of formula: 
wherein R5a, R5b, R5c, R5d each independently are hydrogen, C1-6alkyl or aryl; and aryl is phenyl or phenyl substituted with one, two or three substituents selected from halo, nitro, cyano, amino, hydroxy, C1-4alkyl, C1-4alkyloxy or trifluoromethyl.
In the definitions hereinabove and hereinafter the term halo defines fluoro, chloro, bromo and iodo; C1-4alkyl defines straight and branched chain saturated hydrocarbon radicals having from 1 to 4 carbon atoms such as, for example, methyl, ethyl, propyl, 1-methylethyl, butyl, 2-butyl, 2-methylpropyl, 2,2-dimethylethyl and the like; C1-6alkyl is meant to include C1-4alkyl and the higher homologues thereof having 5 or 6 carbon atoms such as, for example, pentyl, 2-methylbutyl, hexyl, 2-methylpentyl and the like; C3-6alkyl defines straight and branched chain saturated hydrocarbon radicals having from 3 to 6 carbon atoms such as, for example, propyl, 1-methylethyl, butyl, 2-methylpropyl, 2,2-dimethylethyl, pentyl, 2-methylbutyl, hexyl, 2-methylpentyl and the like; C3-7alkenyl defines straight or branched hydrocarbon radicals having one double bond and having from 3 to 7 carbon atoms such as, for example, 2-propenyl, 3-butenyl, 2-butenyl, 2-pentenyl, 3-methyl-2-butenyl, 2-hexenyl, 2-heptenyl and the like, and the carbon atom of said C3-7alkenyl being connected to the nitrogen atom preferably is saturated; C3-7alkynyl defines straight or branched hydrocarbon radicals having one triple bond and having 3 to 7 carbon atoms such as, for example, 2-propynyl, 3-butynyl, 2-butynyl, 2-pentynyl, 3-methyl-2-butynyl, 2-hexynyl, 2-heptynyl and the like, and the carbon atom of said C3-7alkenyl being connected to the nitrogen atom preferably is saturated; C3-7cycloalkyl is generic to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.
The pharmaceutically acceptable acid addition salts as mentioned hereinabove are meant to comprise the therapeutically active non-toxic acid addition salt forms which the compounds of formula (I) are able to form. The latter can conveniently be obtained by treating the base form with such appropriate acids as inorganic acids, for example, hydrohalic acids, e.g. hydrochloric, hydrobromic and the like; sulfuric acid; nitric acid; phosphoric acid and the like; or organic acids, for example, acetic, propanoic, hydroxyacetic, 2-hydroxypropanoic, 2-oxopropanoic, ethanedioic, propanedioic, butanedioic, (Z)-2-butenedioic, (E)-2-butenedioic, 2-hydroxybutanedioic, 2,3-dihydroxybutanedioic, 2-hydroxy-1,2,3-propanetricarboxylic, methanesulfonic, ethanesulfonic, benzenesulfonic, 4-methylbenzenesulfonic, cyclohexanesulfamic, 2-hydroxybenzoic, 4-amino-2-hydroxybenzoic and the like acids. Conversely the salt form can be converted by treatment with alkali into the free base form.
The term addition salt also comprises the hydrates and solvent addition forms which the compounds of formula (I) are able to form. Examples of such forms are e.g. hydrates, alcoholates and the like.
The N-oxide forms of the present compounds are meant to comprise the compounds of formula (I) wherein one or several nitrogen atoms are oxidized to the so-called N-oxide.
Whenever used hereinafter, the term xe2x80x9ccompounds of formula (I)xe2x80x9d is meant to also include their N-oxide forms, their pharmaceutically acceptable acid addition salts, and their stereochemically isomeric forms.
An interesting group of compounds are those compounds of formula (I) for which one or more of the following conditions apply:
1) n is 1 or 2;
2) R1 is halo;
3) R2 is C3-7cycloalkyl or C1-6alkyl;
4) R3 is hydrogen or C1-6alkyl and R4 is hydrogen or C1-6alkyl; or R3 and R4 form a bivalent radical xe2x80x94R3xe2x80x94R4xe2x80x94 of formula (a), (b), (c), (d) or (e), wherein R5 is hydrogen or C1-6alkyl.
Interesting compounds are those compounds of formula (I) wherein n is 1 or 2 and each R1 independently is halo, and more in particular, wherein n is 2 and both R1 are fluoro, especially when the fluor atoms are attached in the 2- and 4-position of the phenyl ring.
Also interesting are those compounds of formula (I) wherein X is N.
Other interesting compounds are those compounds of formula (I) wherein R3 and R4 form a bivalent radical xe2x80x94R3xe2x80x94R4xe2x80x94 of formula (a), (b), (c), (d) or (e) wherein R5a, R5b, R5c and R5d each independently are hydrogen or C1-6alkyl, in particular, xe2x80x94R3xe2x80x94R4xe2x80x94 is a radical of formula (c) wherein both R5a and R5b are hydrogen and R5c and R5d are each independently hydrogen or C1-6alkyl; or a radical of formula (d) wherein both R5a and R5b are C1-6alkyl; or a radical of formula (e) wherein R5a is C1-6alkyl.
Yet another interesting group of compounds are those compounds of formula (I) wherein R2 is C3-7cycloalkyl or C1-6alkyl, in particular wherein R2 is C1-6alkyl, preferably wherein R2 is C3-6alkyl whereby the alkyl chain is branched in the xcex1 position. Said preferred alkyl chains include for example 1-methylethyl and 1-methylpropyl.
A preferred group of compounds are those compounds of formula (I) wherein the phenyl ring attached in the 4-position of the 1,3-dioxolane ring is a 2,4-difluorophenyl ring; and R3 and R4 form a bivalent radical xe2x80x94R3xe2x80x94R4xe2x80x94 of formula (c) wherein both R5a and R5b are hydrogen and R5c and R5d are both hydrogen or are both C1-6alkyl; and R2 is C1-6alkyl.
Also preferred are those compounds of formula (I) wherein the substituents on the 1,3-dioxolane ring have a cis configuration, especially the enantiomerically pure cis isomers.
More preferred are those compounds of formula (I) wherein the phenyl ring attached in the 4-position of the 1,3-dioxolane ring is a 2,4-difluorophenyl ring; and R3 and R4 form a bivalent radical xe2x80x94R3xe2x80x94R4xe2x80x94 of formula (c) wherein R5a, R5b, R5c and R5d are hydrogen; and R2 is methyl, ethyl, propyl, butyl, 1-methylethyl or 1-methylpropyl, especially 1-methylethyl.
Most preferred are 1-[4-[4-[4-[[4-(2,4-difluorophenyl)-4-(1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-2-yl]methoxy]phenyl]-1-piperazinyl]phenyl]-3-(1-methylethyl)-2-imidazolidinone; the N-oxide forms, the pharmaceutically acceptable acid addition salts and stereochemically isomeric forms thereof.
In the following paragraphs there are described different ways of preparing the compounds of formula (I). In order to simplify the structural formulae of the compounds of formula (I) and the intermediates intervening in their preparation, the 2,4,4-trisubstituted moiety will be represented by the symbol T hereinafter. 
The compounds of formula (I) can conveniently be prepared by O-alkylating an appropriately substituted phenol of formula (III) with an alkylating reagent of formula (II). In formula (II) and hereinafter, W represents an appropriate reactive leaving group such as, for example, halo or a sulfonyloxy group. 
Said O-alkylation reaction can conveniently be conducted in a suitable reaction-inert solvent in the presence of an appropriate base and optionally under an inert atmosphere such as, for example, oxygen-free argon or nitrogen gas. Suitable solvents are, for example, hydrocarbons, halogenated hydrocarbons, alkanols, ethers, ketones, esters, dipolar aprotic solvents or a mixture of such solvents. The acid which is liberated during the course of the reaction may be picked up by an appropriate base such as, for example, sodium carbonate, potassium carbonate, sodium hydroxide, sodium hydride and the like; or an amine, e.g., triethylamine. In some instances it may be advantageous to convert the substituted phenol (III) first into a metal salt thereof, e.g. the sodium salt, by the reaction of (III) with a metal base such as, for example, sodium hydride and the like, and to use said metal salt subsequently in the reaction with (II). The reaction mixture may be stirred and heated in order to enhance the rate of the reaction.
In this and the following preparations, the reaction products may be isolated from the medium and, if necessary, further purified according to methodologies generally known in the art such as, for example, extraction, crystallization, trituration and chromatography.
Alternatively, said O-alkylation may be carried out by applying art-known conditions of phase transfer catalysis reactions. Said conditions comprise stirring the reactants, with an appropriate base and optionally under an inert atmosphere as defined hereinabove, in the presence of a suitable phase transfer catalyst. Somewhat elevated temperatures may be appropriate to enhance the rate of the reaction.
The compounds of formula (I) may also be prepared by transacetalating an acetal of formula (V) with a 1,2-diol of formula (IV) by stirring the reactants in an appropriate reaction-inert solvent in the presence of a suitable acid catalyst. 
In formula (V) and hereinafter, each R independently represents an alkyl group or both radicals taken together may also form a bivalent alkanediyl radical such as, for example, 1,2-ethanediyl, 1,3-propanediyl, 2,2-dimethyl-1,3-propanediyl and the like. Suitable acid catalysts are for example, hydrochloric and hydrobromic acid, sulfuric acid and the like, or a sulfonic acid. Appropriate reaction inert solvents are, for example, aromatic hydrocarbons, halogenated hydrocarbons, ethers or a mixture thereof. Said transacetalation reaction can conveniently be conducted at temperatures ranging from about 0xc2x0 C. to about room temperature. In some instances however, the reaction may be conducted at a somewhat elevated temperature, in order to shift the equilibria towards the acetal of formula (I). The alcohol or diol which is liberated during the course of the transacetalation reaction may be removed from the reaction mixture following art-known procedures such as, for example destillation.
The compounds of formula (I) may also be obtained by cyclizing an intermediate of formula (VI) or (IX) with respectively an amine of formula (VII) or (VIII). 
Said cyclization reaction can conveniently be carried out by mixing the reactants, optionally in a reaction-inert solvent such as, for example, water, an aromatic solvent, a alkanol, a ketone, an ester, an ether, a dipolar aprotic solvent or a mixture of such solvents. The addition of an appropriate base such as, for example, sodium carbonate, sodium hydrogen carbonate, potassium carbonate, sodium hydroxide, calcium oxide, sodium acetate, sodium methoxide, sodium hydride, sodium amide and the like, or an organic base such as, for example, triethylamine, may optionally be used to pick up the acid which is formed during the course of the reaction. In some instances the addition of an iodide salt, e.g. potassium iodide; or a crown ether, e.g. 1,4,7,10,13,16-hexa-oxacyclooctadecane, may be appropriate. Stirring and somewhat elevated temperatures may enhance the rate of the reaction.
The compounds of formula (I) may also be obtained by N-alkylating a compound of formula (X) with an alkylating reagent of formula R2xe2x80x94W (XI) wherein R2 and W are as defined hereinabove. 
The compounds of formula (I) wherein R4 is hydrogen, said compounds being represented by formula (I-a), can be prepared by reacting an intermediate of formula (XVII) with an isocyanate R2xe2x80x94Nxe2x95x90Cxe2x95x90O in a reaction-inert solvent such as, for example, dichloromethane. 
Compounds of formula (I) wherein R4 is selected from hydrogen, C1-6alkyl, C3-7cycloalkyl and aryl, said R4 being represented by R4xe2x80x2 and said compounds being represented by formula (I-b), can be prepared by reacting an intermediate of formula (XVIII) wherein L is a suitable leaving group such as, for example, phenoxy, trichloromethoxy, chloro or imidazolyl, with an intermediate NHR2R4xe2x80x2 in a reaction-inert solvent such as, for example, tetrahydrofuran or dichloromethane, and in the presence of an appropriate base such as, for example, triethylamine. Reactive amino groups in R2, in case they are present, are protected with a protective group P such as, for example, a C1-4alkyloxycarbonyl group. Suitably, the reactive amino group may then be deprotected using art-known deprotection techniques to arrive at the desired compound of formula (I-b). 
The compounds of formula (I) may also be converted into each other following art-known transformations.
The compounds of formula (I) may also be converted to the corresponding N-oxide forms following art-known procedures for converting a trivalent nitrogen into its N-oxide form. Said N-oxidation reaction may generally be carried out by reacting the starting material of formula (I) with an appropriate organic or inorganic peroxide. Appropriate inorganic peroxides comprise, for example, hydrogen peroxide, alkali metal or earth alkaline metal peroxides, e.g. sodium peroxide, potassium peroxide; appropriate organic peroxides may comprise peroxy acids such as, for example, benzenecarboperoxoic acid or halo substituted benzenecarboperoxoic acid, e.g. 3-chlorobenzenecarboperoxoic acid, peroxoalkanoic acids, e.g. peroxoacetic acid, alkylhydroperoxides, e.g. tert-butyl hydroperoxide. Suitable solvents are, for example, water, lower alkanols, e.g. ethanol and the like, hydrocarbons, e.g. toluene, ketones, e.g. 2-butanone, halogenated hydrocarbons, e.g. dichloromethane, and mixtures of such solvents.
A number of intermediates and starting materials used in the foregoing preparations are known compounds, while others may be prepared according to art-known methodologies of preparing said or similar compounds. The preparation of the intermediates (II) is described in WO88/05048; the preparation of (III), (VII) and (IX), is described in U.S. Pat. No. 4,619,931, U.S. Pat. No. 4,861,879 and/or EP-A-0,331,232.
In particular, the intermediates of formula (II) can be prepared from intermediates of formula (IV) and acetals of formula (XII), following the transacetalization procedures described hereinabove for the preparation of the compounds of formula (I) from (IV) and (V). The diastereoselectivity of the acetalization can be enhanced in favor of the cis stereoisomer in case W represents a hydroxy moiety. 
The intermediates of formula (IV) can be obtained from an acetal (XIII) by N-alkylation with 1H-imidazole or 1,2,4-triazole, followed by hydrolysis of the acetal (XIV) in an acidic aqueous medium. Alternatively, the hydrolysis of the acetal (XIII) may be performed prior to the N-alkylation with 1H-imidazole or 1,2,4-triazole. 
The intermediate (XIII) in turn can be prepared from a 2-propanone derivative of formula (XV) by treatment with an appropriately substituted Grignard reagent of formula (XVI) followed by base-induced epoxide formation and acetalation with a ketone in the presence of a Lewis acid such as, for example, tin(IV) chloride. 
The intermediates of formula (XVII) wherein R3 is hydrogen, said intermediates being represented by formula (XVII-a), can be prepared by reacting an intermediate of formula (XIX-a) wherein NP2 is a protected amino group wherein P is for example a C1-4alkyloxycarbonyl group, or a functional derivative of NP2 such as, for example, a nitro group, with an intermediate of formula (II) analogous to the procedure described for the reaction of intermediate (II) with intermediate (III). The thus obtained intermediates of formula (XIX-b) may be deprotected according to art-known deprotection techniques. In case NP2 is a nitro group, art-known reduction techniques such as, for example, reduction using hydrogen in the presence of a catalyst, e.g. palladium on activated carbon, may be used to obtain intermediates of formula (XVII-a). Intermediates of formula (XVII) wherein R3 is C1-6alkyl, C3-7cycloalkyl or aryl, said R3 represented by R3xe2x80x2 and said intermediates being represent by formula (XVII-b), can be prepared by reacting an intermediate of formula (XVII-a) with an intermediate Wxe2x80x94R3xe2x80x2 or, in case R3xe2x80x2 is methyl, a functional derivative thereof such as paraformaldehyde together with sodium methanolate, in a reaction-inert solvent such as, for example, methanol, and in the presence of a suitable reducing agent such as, for example, sodiumborohydride. 
Intermediates of formula (XVIII) can be prepared by reacting an intermediate of formula (XVII) with a chloroformate such as, for example, phenylchloroformate or trichloromethylchloroformate, bis(trichloromethyl)carbonate, or with a functional derivative thereof such as, for example, 1,1xe2x80x2-carbonylbis-1H-imidazole. 
It may be convenient to prepare the intermediates of formula (XVIII) and the subsequent compounds of formula (I-b) in the same reaction mixture.
The term xe2x80x9cstereochemically isomeric formsxe2x80x9d as used hereinbefore defines all the possible isomeric forms which the compounds of formula (I) may possess. From formula (I) it is evident that the compounds of this invention have at least two asymmetric carbon atoms in their structures, namely those located in the 2- and 4-position of the dioxolane nucleus. Depending on the nature of the substituents R1 to R5, the compounds of formula (I) may also contain a third or more asymmetric carbon atoms. Consequently the compounds of formula (I) can exist under different stereochemically isomeric forms. Unless otherwise mentioned or indicated, the chemical designation of compounds denotes the mixture of all possible stereo-chemically isomeric forms, said mixtures containing all diastereoisomers and enantiomers of the basic molecular structure.
Pure stereoisomeric forms of the compounds and intermediates as mentioned herein are defined as isomers substantially free of other enantiomeric or diastereomeric forms of the same basic molecular structure of said compounds or intermediates. In particular, the term xe2x80x98stereoisomerically purexe2x80x99 concerns compounds or intermediates having a stereoisomeric excess of at least 80% (i.e. minimum 90% of one isomer and maximum 10% of the other possible isomers) up to a stereoisomeric excess of 100% (i.e. 100% of one isomer and none of the other), more in particular, compounds or intermediates having a stereoisomeric excess of 90% up to 100%, even more in particular having a stereoisomeric excess of 94% up to 100% and most in particular having a stereoisomeric excess of 97% up to 100%. The terms xe2x80x98enantiomerically purexe2x80x99 and xe2x80x98diastereomerically purexe2x80x99 should be understood in a similar way, but then having regard to the enantiomeric excess, respectively the diastereomeric excess of the mixture in question.
The absolute configuration of each asymmetric center may be indicated by the stereochemical descriptors R and S, this R and S notation corresponding to the rules described in Pure Appl. Chem. 1976, 45, 11-30. The terms cis and trans are used herein in accordance with Chemical Abstracts nomenclature (J. Org. Chem. 1970, 35 (9), 2849-2867), and refer to the position of the substituents on a ring moiety, more in particular on the dioxolane ring in the compounds of formula (I). For instance, when establishing the cis or trans configuration of the dioxolane ring, the substituent with the highest priority on the carbon atom in the 2 position of the dioxolane ring, and the substituent with the highest priority on the carbon atom in the 4 position of the dioxolane ring are considered (the priority of a substituent being determined according to the Cahn-Ingold-Prelog sequence rules). When said two substituents with highest priority are at the same side of the ring then the configuration is designated cis, if not, the configuration is designated trans.
For instance, the absolute configuration of the asymmetric carbon atoms of compound 51 as described in example B.3 hereinafter, i.e. (2S-cis)-1-[4-[4-[4-[[4-(2,4-difluorophenyl)-4-(1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-2-yl]methoxy]phenyl]-1-piperazinyl]phenyl]-3-(1-methylethyl)-2-imidazolidinone, is as depicted hereinbelow. Thus, carbon atom number 2 of the dioxolane ring in this compound has the S configuration and carbon number 4 has the R configuration. 
Pure stereoisomeric forms of the compounds and the intermediates of this invention may be obtained by the application of art-known procedures. For instance, enantiomers may be separated from each other by the selective crystallization of their diastereomeric salts with optically active acids. Alternatively, enantiomers may be separated by chromatographic techniques using chiral stationary phases. Said pure stereochemically isomeric forms may also be derived from the corresponding pure stereochemically isomeric forms of the appropriate starting materials, provided that the reaction occurs stereospecifically. Preferably if a specific stereoisomer is desired, said compound will be synthesized by stereospecific methods of preparation. These methods will advantageously employ enantiomerically pure starting materials. Stereochemically isomeric forms of the compounds of formula (I) are obviously intended to be included within the scope of the invention.
The diastereomeric racemates of (I) can be obtained separately by conventional methods. Appropriate physical separation methods which may advantageously be employed are, for example, selective crystallization and chromatography, e.g., column chromatography.
Since the stereochemical configuration is already fixed in a number of intermediate compounds, e.g., in the intermediates of formulae (II), (VI), (VIII) and (X) and some of their respective precursors, it is also possible to separate cis and trans forms at one of these stages. The separation of cis and trans forms of such intermediates may be performed by conventional methods as mentioned hereinabove for the separation of the cis and trans forms of the compounds of formula (I). The corresponding diastereomeric forms of (I) may then be derived thereform in the previously indicated manner.
It is evident that the cis and trans racemates may be further resolved into their optical isomers, cis(+) and cis(xe2x88x92), respectively trans(+) and trans(xe2x88x92) by the application of art-known methodologies. In case additional asymmetric centra are present in the abovementioned intermediates and/or compounds, the resulting mixtures of stereoisomers may be further separated by the previously indicated methodologies. Preferably, if a specific stereochemical form is desired, said compound will be synthesized by stereoselective methods of preparation, which will advantageously employ enantiomerically pure starting materials.
The compounds of formula (I), the pharmaceutically acceptable addition salts and the stereochemically isomeric forms thereof are useful agents for combating fungi in vivo. The present compounds are found to be active against a wide variety of fungi, such as Candida spp., e.g. Candida albicans, Candida glabrata, Candida krusei, Candida parapsilosis, Candida kefyr, Candida tropicalis; Aspergillus spp., e.g. Aspergillus fumigatus, Aspergillus niger, Aspergillus flavus; Cryptococcus neoformans; Sporothrix schenckii; Epidermophyton floccosum; Microsporum canis; Trichophyton spp., e.g. Trichophyton mentagrophytes, Trichophyton rubrum, Trichophyton quinckeanum; and several dematiaceous hyphomycetes.
The compounds of the present invention show enhanced antifungal activity against some fungal isolates and have a good oral availability. In vitro experiments such as the determination of fungal susceptibility of the present compounds for, for instance, Candida and dermatophyte isolates, and the determination of the effects of the present compounds on the sterol synthesis in, for instance, Candida albicans and Trichophyton mentagrophytes, demonstrate their antifungal potency. Also in vivo experiments in several mouse, guinea-pig and rat models, for instance, oral administration of a test compound to mice infected with Trichophyton quinckeanum or Microsporum canis, show that the present compounds are potent antifungals. The example hereinbelow demonstrates the in vitro antifungal activity of the present compounds versus Candida kefyr and Trichophyton rubrum. 
In view of the utility of the compounds of formula (I), there is provided a method of treating warm-blooded animals, including humans, suffering from fungal infections. Said method comprises the systemic administration of an effective amount of a compound of formula (I), a N-oxide form, a pharmaceutically acceptable addition salt or a possible stereoisomeric form thereof, to warm-blooded animals, including humans. Hence, compounds of formula (I) are provided for use as a medicine, in particular, the use of a compound of formula (I) in the manufacture of a medicament useful in treating fungal infections is provided.
In general, it is contemplated that a therapeutically effective daily amount would be from 0.05 mg/kg to 20 mg/kg body weight.
The present invention also provides compositions for treating or preventing fungal infections comprising a therapeutically effective amount of a compound of formula (I) and a pharmaceutically acceptable carrier or diluent.
In view of their useful pharmacological properties, the subject compounds may be formulated into various pharmaceutical forms for systemic or topical administration purposes.
To prepare the pharmaceutical compositions of this invention, a therapeutically effective amount of a particular compound, in base or addition salt form, as the active ingredient is combined in intimate admixture with a pharmaceutically acceptable carrier, which carrier may take a wide variety of forms depending on the form of preparation desired for administration. These pharmaceutical compositions are desirably in unitary dosage form suitable, preferably, for administration orally, rectally. percutaneously, or by parenteral injection.
For example, in preparing the compositions in oral dosage form, any of the usual pharmaceutical media may be employed, such as, for example, water, glycols, oils, alcohols and the like in the case of oral liquid preparations such as suspensions, syrups, elixirs and solutions: or solid carriers such as starches, sugars, kaolin, lubricants, binders, disintegrating agents and the like in the case of powders, pills, capsules and tablets. Because of their ease in administration, tablets and capsules represent the most advantageous oral dosage unit form, in which case solid pharmaceutical carriers are obviously employed. As appropriate compositions for topical application there may be cited all compositions usually employed for topically administering drugs e.g. creams, gel, dressings, shampoos, tinctures, pastes, ointments, salves, powders and the like. In particular, the present compounds may be formulated in topical compositions specially adapted for delivery to the nail. In the compositions suitable for percutaneous administration, the carrier optionally comprises a penetration enhancing agent and/or a suitable wetting agent, optionally combined with suitable additives of any nature in minor proportions, which additives do not cause a significant deleterious effect to the skin. Said additives may facilitate the administration to the skin and/or may be helpful for preparing the desired compositions. These compositions may be administered in various ways, e.g., as a transdermal patch, as a spot-on, as an ointment. For parenteral compositions, the carrier will usually comprise sterile water, at least in large part. Injectable solutions, for example, may be prepared in which the carrier comprises saline solution, glucose solution or a mixture of saline and glucose solution. Injectable suspensions may also be prepared in which case appropriate liquid carriers, suspending agents and the like may be employed.
In order to enhance the solubility and/or the stability of the compounds of formula (I) in pharmaceutical compositions, it can be advantageous to employ xcex1-, xcex2- or xcex3-cyclodextrins or their derivatives. Also co-solvents such as alcohols may improve the solubility and/or the stability of the compounds of formula (I) in pharmaceutical compositions. In the preparation of aqueous compositions, addition salts of the subject compounds are obviously more suitable due to their increased water solubility.
Appropriate cyclodextrins are xcex1-, xcex2-, xcex3-cyclodextrins or ethers and mixed ethers thereof wherein one or more of the hydroxy groups of the anhydroglucose units of the cyclodextrin are substituted with C1-6alkyl, particularly methyl, ethyl or isopropyl, e.g. randomly methylated xcex2-CD; hydroxyC1-6alkyl, particularly hydroxyethyl, hydroxypropyl or hydroxybutyl; carboxyC1-6alkyl, particularly carboxymethyl or carboxyethyl; C1-6alkylcarbonyl, particularly acetyl; C1-6alkyloxycarbonylC1-6alkyl or carboxy-C1-6alkyloxyC1-6alkyl, particularly carboxymethoxypropyl or carboxyethoxypropyl; C1-6alkylcarbonyloxyC1-6alkyl, particularly 2-acetyloxypropyl. Especially noteworthy as complexants and/or solubilizers are xcex2-CD, randomly methylated xcex2-CD, 2,6-dimethyl-xcex2-CD, 2-hydroxyethyl-xcex2-CD, 2-hydroxyethyl-xcex3-CD, 2-hydroxypropyl-xcex3-CD and (2-carboxymethoxy)propyl-xcex2-CD, and in particular 2-hydroxypropyl-xcex2-CD (2-HP-xcex2-CD).
The term mixed ether denotes cyclodextrin derivatives wherein at least two cyclodextrin hydroxy groups are etherified with different groups such as, for example, hydroxy-propyl and hydroxyethyl.
The average molar substitution (M.S.) is used as a measure of the average number of moles of alkoxy units per mole of anhydroglucose. The M.S. value can be determined by various analytical techniques such as nuclear magnetic resonance (NMR), mass spectrometry (MS) and infrared spectroscopy (IR). Depending on the technique used, slightly different values may be obtained for one given cyclodextrin derivative. Preferably, as measured by mass spectrometry, the M.S. ranges from 0.125 to 10.
The average substitution degree (D.S.) refers to the average number of substituted hydroxyls per anhydroglucose unit. The D.S. value can be determined by various analytical techniques such as nuclear magnetic resonance (NMR), mass spectrometry (MS) and infrared spectroscopy (IR). Depending on the technique used, slightly different values may be obtained for one given cyclodextrin derivative. Preferably, as measured by mass spectrometry, the D.S. ranges from 0.125 to 3.
An interesting way of formulating the present compounds in combination with a cyclodextrin or a derivative thereof has been described in EP-A-721,337. The formulations described therein are particularly suitable for oral administration and comprise an antifungal as active ingredient, a sufficient amount of a cyclodextrin or a derivative thereof as a solubilizer, an aqueous acidic medium as bulk liquid carrier and an alcoholic co-solvent that greatly simplifies the preparation of the composition. Said formulations may also be rendered more palatable by adding pharmaceutically acceptable sweeteners and/or flavours.
Other convenient ways to enhance the solubility of the compounds of the present invention in pharmaceutical compositions are described in WO-94/05263, PCT application No. PCT/EP98/01773, EP-A-499,299 and WO 97/44014.
More in particular, the present compounds may be formulated in a pharmaceutical composition comprising a therapeutically effective amount of particles consisting of a solid dispersion comprising
(a) a compound of formula (I), and
(b) one or more pharmaceutically acceptable water-soluble polymers.
The term xe2x80x9ca solid dispersionxe2x80x9d defines a system in a solid state (as opposed to a liquid or gaseous state) comprising at least two components, wherein one component is dispersed more or less evenly throughout the other component or components. When said dispersion of the components is such that the system is chemically and physically uniform or homogenous throughout or consists of one phase as defined in thermo-dynamics, such a solid dispersion is referred to as xe2x80x9ca solid solutionxe2x80x9d. Solid solutions are preferred physical systems because the components therein are usually readily bioavailable to the organisms to which they are administered.
The term xe2x80x9ca solid dispersionxe2x80x9d also comprises dispersions which are less homogenous throughout than solid solutions. Such dispersions are not chemically and physically uniform throughout or comprise more than one phase.
The water-soluble polymer in the particles is a polymer that has an apparent viscosity of 1 to 100 mPa.s when dissolved in a 2% aqueous solution at 20xc2x0 C. solution.
Preferred water-soluble polymers are hydroxypropyl methylcelluloses or HPMC. HPMC having a methoxy degree of substitution from about 0.8 to about 2.5 and a hydroxypropyl molar substitution from about 0.05 to about 3.0 are generally water-soluble. Methoxy degree of substitution refers to the average number of methyl ether groups present per anhydroglucose unit of the cellulose molecule. Hydroxy-propyl molar substitution refers to the average number of moles of propylene oxide which have reacted with each anhydroglucose unit of the cellulose molecule.
The particles as defined hereinabove can be prepared by first preparing a solid dispersion of the components, and then optionally grinding or milling that dispersion. Various techniques exist for preparing solid dispersions including melt-extrusion, spray-drying and solution-evaporation, melt-extrusion being preferred.
It may further be convenient to formulate the present azole antifungals in the form of nanoparticles which have a surface modifier adsorbed on the surface thereof in an amount sufficient to maintain an effective average particle size of less than 1000 nm. Useful surface modifiers are believed to include those which physically adhere to the surface of the antifungal agent but do not chemically bond to the antifungal agent.
Suitable surface modifiers can preferably be selected from known organic and inorganic pharmaceutical excipients. Such excipients include various polymers, low molecular weight oligomers, natural products and surfactants. Preferred surface modifiers include nonionic and anionic surfactants.
Yet another interesting way of formulating the present compounds involves a pharmaceutical composition whereby the present antifungals are incorporation in hydrophilic polymers and applying this mixture as a coat film over many small beads, thus yielding a composition with good bioavailability which can conveniently be manufactured and which is suitable for preparing pharmaceutical dosage forms for oral administration.
Said beads comprise (a) a central, rounded or spherical core, (b) a coating film of a hydrophilic polymer and an antifungal agent and (c) a seal-coating polymer layer.
Materials suitable for use as cores in the beads are manifold, provided that said materials are pharmaceutically acceptable and have appropriate dimensions and firmness. Examples of such materials are polymers, inorganic substances, organic substances, and saccharides and derivatives thereof.
The cores in said beads may have a diameter of about 60 mesh, corresponding to about 250 xcexcm, or larger. Particular beads having a 25-30 mesh core (600-710 xcexcm) are disclosed in WO-94/05263. PCT/EP98/01773 discloses beads of which the core has a diameter of about 250 to about 600 (30-60 mesh).
It is especially advantageous to formulate the aforementioned pharmaceutical compositions in dosage unit form for ease of administration and uniformity of dosage. Dosage unit form as used in the specification and claims herein refers to physically discrete units suitable as unitary dosages, each unit containing a predetermined quantity of active ingredient calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. Examples of such dosage unit forms are tablets (including scored or coated tablets), capsules, pills, powder packets, wafers, injectable solutions or suspensions, teaspoonfuls, tablespoonfuls and the like, and segregated multiples thereof.
Also, it may be convenient to combine the present antifungal compounds with other antifungals such as, for example, azole containing antifungals, e.g. bifoconazole, crococonazole, clotrimazole, eberconazole, econazole, fenticonazole, fluconazole, flutrimazole, isoconazole, itraconazole, ketoconazole, lanoconazole, miconazole, neticonazole, omoconazole, oxiconazole, saperconazole, SCH 39304, sertaconazole, sulconazole, tioconazole, voriconazole; or non-azole antifungals, e.g. amorolfine, butenafine, ciclopirox, cioteronel, naftidine, isotretinoin, rimoprogin, terbinafine. It is particularly useful to combine the present compounds with other dermatological antifungals.
The combination of an antifungal compound and a compound of formula (I) can be used as a medicine. Thus, the present invention also relates to a product containing (a) a compound of formula (I), and (b) another antifungal compound, as a combined preparation for simultaneous, separate or sequential use in antifungal treatment.
The different drugs in such products may be combined in a single preparation together with pharmaceutically acceptable carriers. Alternatively, such products may comprise, for example, a kit comprising a container with a suitable composition containing a compound of formula (I) and another container with a composition containing another antifungal. Such a product may have the advantage that a physician can select on the basis of the diagnosis of the patient to be treated the appropriate amounts of each component and the sequence and timing of the administration thereof.